title: A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.
abstract: Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4×10⁻¹⁴). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38× coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland ; DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.forename: Jeanette
authors.initials: J
authors.lastname: Bannoehr
authors.forename: Philippe
authors.initials: P
authors.lastname: Plattet
authors.forename: Regula
authors.initials: R
authors.lastname: Hauswirth
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Michaela
authors.initials: M
authors.lastname: Drögemüller
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Wiener
authors.forename: Marcus
authors.initials: M
authors.lastname: Doherr
authors.forename: Marta
authors.initials: M
authors.lastname: Owczarek-Lipska
authors.forename: Arnaud
authors.initials: A
authors.lastname: Galichet
authors.forename: Monika M
authors.initials: MM
authors.lastname: Welle
authors.forename: Katarina
authors.initials: K
authors.lastname: Tengvall
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bergvall
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rüfenacht
authors.forename: Monika
authors.initials: M
authors.lastname: Linek
authors.forename: Manon
authors.initials: M
authors.lastname: Paradis
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.forename: Petra
authors.initials: P
authors.lastname: Roosje
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D004283:Dog Diseases / Q000209:etiology / Q000235:genetics*; D004285:Dogs; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008780:Methyltransferases / Q000235:genetics; D009154:Mutation; D009666:Nose; D010241:Parakeratosis / Q000235:genetics* / Q000473:pathology
chemical_list: D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C515701:SUV39H2 protein, human